Streptogramin derivatives, their preparation and pharmaceutical compositions which contain them

ABSTRACT

Streptogramine derivatives of general formula (I) below, wherein the radical R 1  is a methyl or ethyl radical, the radical R 2  is a bromine or chlorine atom, or is an alkenyl radical with 3 to 5 carbon atoms when R 3  and R 4  are methyl, and one of R 3  and R 4  is a hydrogen atom or a methyl radical and the other is a methyl radical are disclosed. The streptogramine derivatives of general formula (I) have particularly useful antibacterial properties, and may be used in combination with a pristinamycin II derivative. ##STR1##

This application is a national stage application filed under 35 U.S.C. §371 and claims priority of International application numberPCT/FR95/01025, filed Jul. 31, 1995.

The present invention relates to streptogramin derivatives of generalformula: ##STR2## in which the radical R₁ denotes a methyl or ethylradical,

the radical R₂ denotes a chlorine or bromine atom or denotes an alkenylradical containing 3 to 5 carbon atoms if R₃ and R₄ are methyl radicalsand

the symbols R₃ and R₄ are: one, a hydrogen atom or a methyl radical and,the other, a methyl radical.

Soluble derivatives belonging to the group B of streptogramins weredescribed previously in European Patent Applications EP 133 097 and EP248 703. However, by themselves or used in combination with asynergizing component of group A, these derivatives are active only byinjectable route and are not, or not very, active orally.

The derivatives of the general formula (I) which are defined above thusopen the way to new streptogramins intended for an oral treatment.

According to the invention the streptogramins of general formula (I) inthe case of which R₂ is a chlorine or bromine atom can be obtained bythe action of the corresponding N-halosuccinimide derivative onpristinamycin I in the case of which R₂ is a hydrogen atom.

The reaction is performed by means of N-chloro- or N-bromosuccinimide inan organic solvent like, for example, a chlorinated solvent(dichloromethane, dichloroethane, chloroform) or a nitrile(acetonitrile), at a temperature of between 20 and the refluxtemperature of the solvent employed.

According to the invention the streptogramins of general formula (I) inthe case of which R₂ is an alkenyl radical containing 3 to 5 carbonatoms can be obtained by rearrangement in a slightly basic medium of asalt derived from 4-N-alkenylammonio pristinamycin IA of generalformula: ##STR3## in which R₁ is defined as above, R₅, R₆, R₇ and R₈ area hydrogen atom or a methyl radical, provided that at least 2 of themare hydrogen atoms, and X.sup.Θ denotes an anion, to give the derivativeof general formula: ##STR4## in the case of which R₁, R₅, R₆, R₇ and R₈are defined as above.

The reaction is performed by heating at a temperature of between 80° and100° C. in an aqueous or two-phase medium (for example in ethylacetate/water medium) in the presence of sodium acetate or of sodium orpotassium bicarbonate. A halide of 4-N-alkenylammonio pristinamycin IAis advantageously employed.

The halide of 4-N-alkenylammonio pristinamycin IA can be obtained by theaction of an alkenyl halide of general formula: ##STR5## in the case ofwhich R₅, R₆, R₇ and R₈ are defined as above and Hal denotes a halogenatom, on a pristinamycin derivative of general formula: ##STR6## inwhich R₁ is defined as above.

The reaction is advantageously performed in an organic solvent such as achlorinated solvent (for example dichloromethane, dichloroethane,chloroform) or an alcohol (for example ethanol) or in a mixture, at atemperature of between 20° C. and the reflux temperature of the reactionmixture. Preferably, a product of general formula (IV) in the case ofwhich Hal is a chlorine or bromine atom is reacted.

The products of general formula (V) are known products, which aredescribed by J. Preud'Homme, P. Tarridec, and A. Belloc, Bull. Soc.Chim. Fr., 2, 585 (1968).

The new streptogramin derivatives of general formula (I) can bepurified, if appropriate, by physical methods such as crystallization orchromatography.

The streptogramin derivatives according to the present invention exhibitantibacterial properties and properties of synergizing the antibacterialactivity of the derivatives of pristinamycin II.

In vivo, it has been shown that they synergize the antimicrobialactivity of pristinamycin II_(B) on the experimental infections of themouse with Staphylococcus aureus IP 8203 in doses of between 30 and 150mg/kg orally (30/70 combination).

Their toxicity (LD50) is higher than 1000 mg/kg orally.

The following examples illustrate the preparation of the productsaccording to the invention.

In the examples which follow, the NMR spectra were investigated indeuterochloroform, the nomenclature employed is that of J. O. Anteuniset al., Eur. Biochem., 58, 259 (1975) and especially: ##STR7## forexample, the protons at 4δ and 4ε are respectively named as H₂, H₃ ofthe aromatic at 4; the flash chromatographies are performed according toW. C. Still et al., J. Org. Chem., 43, 2923 (1978), at a mean nitrogenpressure of 50 kPa using a silica of 40-53 μm particle size; in allcases the flash chromatography follow-up is carried out using thin layerchromatography.

EXAMPLE 1

4ε-chloro pristinamycin I_(A).

8 g of pristinamycin IA in 80 cm³ of acetonitrile are placed in a roundbottom flask and 1.39 g of N-chlorosuccinimide are then added. Themixture is heated to reflux for 16 hours 30 minutes and then 0.12 g ofN-chlorosuccinimide are added and the reflux is continued for 3 hours.The reaction mixture is concentrated to dryness at reduced pressure (2.7kPa) at 30° C. The solid obtained is taken up with 50 cm³ ofdichloromethane and 60 cm³ of distilled water to which sodium chloridehas been added, the aqueous phase is separated off and then the organicphase is washed with 50 cm³ of distilled water saturated with sodiumchloride. The organic phase is separated off, dried over magnesiumsulphate, filtered and then concentrated to dryness at reduced pressure(2.7 kPa) at 30° C. to give a yellow solid which is recrystallized from100 cm³ of 1-propanol at reflux and then a second time from 50 cm³ of1-propanol at reflux. After cooling, filtration of the crystals anddrying at reduced pressure (135 Pa) at 50° C. 3 g of 4ε-chloropristinamycin I_(A) are obtained in the form of light-beige crystalsmelting at 220° C.

Proton N.M.R. spectrum (300 MHz, CDCl₃, δ in ppm): 0.58 (dd, J=16 and 6Hz, 1H, 5 β₂), 0.91 (t, J=7.5 Hz, 3H: CH₃ 2 γ), from 1.05 to 1.35 (mt,2H: 3 β₂ and 3 γ₂), 1.32 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from 1.50 to 1.85(mt, 3H: 3 γ₁ and CH₂ 2 β), 2.03 (mt, 1H, 3 β₁), 2.17 (mt, 1H, 5 δ₂),2.39 (broad d, J=16 Hz, 1H: 5 δ₁), 2.44 (d, J=16 Hz, 1H: 5 β₁), 2.77 (s,6H: N(CH₃)₂ 4), 2.85 (dt, J=13.5 and 4.5 Hz, 1H: 5 ε₂), 2.97 (dd, J=12and 5 Hz, 1H: 4 β₂), 3.23 (s, 3H: NCH₃ 4), 3.35 (t, J=12 Hz, 1H: 4 β₁),3.30 and 3.58 (2 mts, each 1H: CH₂ 3 δ) , 4.57 (dd, J=8 and 7.5 Hz: 1H,3 α), 4.76 (broad dd, J=13.5 and 8 Hz, 1H: 5 ε₁), 4.85 (mt, 1H: 2α),4.90 (dd, J=10 and 1.5 Hz, 1H: 1α), 5.25 (dd, J=12 and 5 Hz, 1H: 4 α),5.31 (broad d, J=6 Hz, 1H: 5 α), 5.86 (d, J=9.5 Hz, 1H: 6 α), 5.90 (mt,1H: 1 β), 6.50 (d, J=10 Hz, 1H: NH 2), 6.97 (d, J=8 Hz, 1H: H 5 of thearomatic at 4), 7.08 (dd, J=8 and 2 Hz, 1H: H 6 of the aromatic at 4),from 7.15 to 7.40 (mt, 6H: aromatics H 6 and H 2 of the aromatic at 4),7.43 (dd, J=8.5 and 2 Hz, 1H: 1' H₄), 7.52 (dd, J=8.5 and 4.5 Hz, 1H: 1'H₅), 7.83 (dd, J=4.5 and 2 Hz, 1H: 1' H₆), 8.38 (d, J=10 Hz, 1H: NH 1),8.73 (d, J=9.5 Hz, 1H: NH 6), 11.65 (s, 1H: OH).

EXAMPLE 2

4ε-bromo pristinamycin I_(A)

30 g of pristinamycin I_(A) in 300 cm³ of dichloromethane are placed ina round bottom flask and then 6.85 g of N-bromosuccinimide are added.The mixture is stirred at ambient temperature for 29 hours and thenconcentrated to dryness at reduced pressure. The solid obtained isstirred in 400 cm³ of diethyl ether, filtered off and then washed with 2times 100 cm³ of diethyl ether. After filtration the solid is ground upfor 45 minutes in 400 cm³ of distilled water, filtered off and thenwashed with 2 times 150 cm³ of water. The solid obtained is dried andthen recrystallized from 1600 cm³ of ethanol at reflux. After cooling,filtration of the crystals and drying at reduced pressure (135 Pa) at50° C. 23.2 g of 4ε-bromo pristinamycin I_(A) are obtained in the formof white crystals melting at 220° C.

Proton N.M.R spectrum (300 MHz, CDCl₃, δ in ppm) : 0.58 (dd, J=16 and 6Hz, 1H, 5 β₂), 0.91 (t, J=7.5 Hz, 3H: CH₃ 2 γ), from 1.10 to 1.40 (mt,2H: 3 β₂ and 3 γ₂) 1.32 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from 1.50 to 1.85(mt, 3H: 3 γ₁ and CH₂ 2 β), 2.03 (mt, 1H, 3 β₁), 2.19 (mt, 1H, 5 δ₂),2.39 (broad d, J=16 Hz, 1H: 5 δ₁), 2.44 (d, J=16 Hz, 1H: 5 β₁), 2.76 (s,6H: N(CH₃)₂ 4), 2.83 (dt, J=13.5 and 4 Hz, 1H: 5 ε₂), 2,97 (dd, J=12.5and 4.5 Hz, 1H: 4 β₂), 3.23 (s, 3H: NCH₃ 4), 3.30 and 3.57 (2 mts, each1H: CH₂ 3 δ), 3.33 (t, J=12.5 Hz, 1H: 4 β₁), 4.55 (dd, J=8 and 7.5 Hz,1H, 3 α), 4.74 (broad dd, J=13.5 and 8 Hz, 1H: 5 ε₁), 4.84 (mt, 1H: 2α),4.92 (dd, J=10 and 2 Hz, 1H: 1α), 5.27 (dd, J=12.5 and 4.5 Hz, 1H: 4 α),5.33 (broad d, J=6 Hz, 1H: 5 α), 5.88 (d, J=9.5 Hz, 1H: 6 α), 5.90 (mt,1H: 1β), 6.53 (d, J=10 Hz, 1H: NH 2), 7.00 (d, J=8 Hz, 1H: H 5 of thearomatic at 4), 7.12 (dd, J=8 and 2 Hz, 1H: H 6 of the aromatic at 4),from 7.15 to 7.40 (mt, 5H: aromatic H 6), 7.43 (dd, J=8.5 and 2 Hz, 1H:1' H₄), 7.46 (d, J=2 Hz, 1H: H 2 of the aromatic at 4), 7.52 (dd, J=8.5and 4.5 Hz, 1H: I' H₅), 7.87 (dd, J=4.5 and 2 Hz, 1H: 1' H₆), 8.41 (d,J=10 Hz, 1H: NH 1), 8.74 (d, J=9.5 Hz, 1H: NH 6), 11.65 (s, 1H: OH).

EXAMPLE 3

4ε-chloro pristinamycin I_(B)

By operating as in Example 1 but starting from 1.7 g of pristinamycinI_(B), 320 mg of N-chlorosuccinimide in 17 cm³ of acetonitrile and after1 hour 30 minutes of reflux and then concentration of the reactionmixture to dryness, 1.8 g are obtained of a beige solid which ispurified by flash chromatography (98/2 dichloromethane/methanol eluent),to give 1.2 g of 4ε-chloro pristinamycin I_(B) in the form of a paleyellow solid melting at 198° C.

Proton N.M.R spectrum (400 MHz, CDCl₃, δ in ppm): 0.79 (dd, J=16 and 5.5Hz, 1H, 5 β₂), 0.91 (t, J=7.5 Hz, 3H: CH₃ 2 γ), 1.15 (mt, 1H: 3 β₂),from 1.25 to 1.40 (mt, 1H: 3 γ₂), 1.34 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from1.50 to 1.85 (mt, 3H: 3 γ₁ and CH₂ 2 β), 2.03 (mt, 1H, 3 β₁) 2.23 (mt,1H, 5 δ₂), 2.40 (broad d, J=16 Hz, 1H: 5 δ₁), 2.47 (d, J=16 Hz, 1H: 5β₁), 2.85 (dt, J=13 and 4 Hz, 1H: 5 ε₂) from 2.85 to 2.90 (mt, 1H: 4β₂), 2,88 (s, 3H: ArNCH₃ 4), 3.25 (s, 3H: NCH₃ 4), 3.28 and 3.58 (2 mts,each 1H: CH₂ 3 δ), 3.31 (t, J=12 Hz, 1H: 4 β₁), 4.40 (mf, 1H: ArNH),4.57 (t, J=7.5 Hz, 1H: 3 α), 4.78 (broad dd, J=13 and 8 Hz, 1H: 5 ε₁),4.84 (mt, 1H: 2α), 4.91 (broad d, J=10 Hz, 1H: 1α), 5.23 (dd, J=12 and 5Hz, 1H: 4 α), 5.36 (broad d, J=5.5 Hz, 1H: 5 α), 5.89 (d, J=9.5 Hz, 1H:6 α), 5.90 (mt, 1H: 1β), 6.51 (d, J=10 Hz, 1H: NH 2), 6.55 (d, J=8 Hz,1H: H 5 of the aromatic at 4), 7.0.2 (dd, J=8 and 2 Hz, 1H: H 6 of thearomatic at 4), 7.13 (d, J=2 Hz, 1H: H 2 of the aromatic at 4), from7.15 to 7.40 (mt, 5H: aromatic H 6), 7.43 (broad d, J=8.5 Hz, 1H: 1'H₄), 7.52 (dd, J=8.5 and 4.5 Hz, 1H: 1' H₅), 7.79 (broad d, J=4.5 Hz,1H: 1' H₆), 8.40 (d, J=10 Hz, 1H: NH 1), 8.75 (d, J=9.5 Hz, 1H: NH 6),11.63 (s, 1H: OH).

EXAMPLE 4

4ε-bromo pristinamycin I_(B)

By operating as in Example 2 but starting from 2 g of pristinamycinI_(B), 420 mg of N-bromosuccinimide in 30 cm³ of dichloromethane andafter 1 hour 30 minutes' stirring at ambient temperature and thenconcentration of the reaction mixture to dryness, 2.1 g are obtained ofa beige solid which is purified by flash chromatography (98/2dichloromethane/methanol eluent) to give 1.7 g of 4ε-bromo pristinamycinI_(B) in the form of a white solid melting at 220° C.

Proton N.M.R. spectrum (400 MHz, CDCl₃, δ in ppm): 0.80 (dd, J=16 and5.5 Hz, 1H, 5 β₂), 0.90 (t, J=7.5 Hz, 3H: CH₃ 2 γ), 1.13 (mt, 1H: 3 β₂),from 1.20 to 1.40 (mt, 1H: 3 γ₂), 1.33 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from1.50 to 1.85 (mt, 3H: 3 γ₁ and CH₂ 2 β), 2.03 (mt, 1H, 3 β₁), 2.28 (mt,1H, 5 δ₂), 2.40 (broad d, J=16 Hz, 1H: 5 δ₁), 2.46 (d, J=16 Hz, 1H: 5β₁), 2.85 (dt, J=13 and 5 Hz, 1H: 5 ε₂), 2.88 (d, J=5.5 Hz, 3H: ArNCH₃4), 2.90 (dd, J=12 and 4 Hz, 1H: 4 β₂), 3.24 (s, 3H: NCH₃ 4), 3.30 and3.58 (2 mts, each 1H: CH₂ 3 δ), 3.31 (t, J=12 Hz, 1H: 4 β₁) 4.41 (q,J=5.5 Hz, 1H: ArNH), 4.57 (t, J=7.5 Hz, 1H: 3 α), 4.78 (broad dd, J=13and 8 Hz, 1H: 5 ε₁), 4.85 (mt, 1H: 2α), 4.91 (broad d, J=10 Hz, 1H: 1α),5.24 (dd, J=12 and 4 Hz, 1H: 4 α), 5.37 (broad d, J=5.5 Hz, 1H: 5 α),5.89 (d, J=9.5 Hz, 1H: 6 α), 5.90 (mt, 1H: 1β), 6.51 (d, J=10 Hz, 1H: NH2), 6.53 (d, J=8 Hz, 1H: H 5 of the aromatic at 4), 7.0.5 (dd, J=8 and 2Hz, 1H: H 6 of the aromatic at 4), from 7.15 to 7.40 (mt, 6H: aromatic H6 and H 2 of the aromatic at 4), 7.43 (broad d, J=8.5 Hz, 1H: 1' H₄),7.48 (dd, J=8.5 and 5 Hz, 1H: 1' H₅), 7.79 (broad d, J=5 Hz, 1H: 1' H₆),8.40 (d, J=10 Hz, 1H: NH 1), 8.76 (d, J=9.5 Hz, 1H: NH 6), 11.63 (s, 1H:OH).

EXAMPLE 5

4ε-allyl pristinamycin IA

7.07 g of sodium acetate in 100 cm³ of distilled water are placed in athree-necked flask kept under a nitrogen atmosphere. The solution isbrought to reflux and then a solution of 15.5 g of 4-N-allylammoniopristinamycin I_(A) bromide in 100 cm³ of distilled water is added via adropping funnel. After 2 hours' reaction 1 g of sodium acetate is addedand the mixture is stirred for 22 hours at reflux. A new portion of 5 gof sodium acetate is added and the reaction is continued for 20 hours.The precipitate formed is filtered off hot, rinsed with 2 times 50 cm³of distilled water and then dried at reduced pressure (2.75 kPa) to give7 g of a white solid, which is purified by flash chromatography (70/30toluene/acetone eluent) to give 4.6 g of 4ε-allyl pristinamycin I_(A) inthe form of a white solid melting at 160° C.

Proton N.M.R. spectrum (400 MHz, CDCl₃, δ in ppm): 0.42 (dd, J=16 and5.5 Hz, 1H, 5 β₂), 0.92 (t, J=7.5 Hz, 3H: CH₃ 2 γ), from 1.15 to 1.40(mt, 2H: 3 β₂ and 3 γ₂), 1.33 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from 1.55 to1.80 (mt, 3H: 3 γ₁ and CH₂ 2 β), from 2.00 to 2.15 (mt, 2H, 3 β₁ and 5δ₂), 2.30 (broad d, J=16 Hz, 1H: 5 δ₁), 2.33 (d, J=16 Hz, 1H: 5 β₁) 2.63(s, 6H: N(CH₃)₂ 4), 2.76 (dt, J=13.5 and 4.5 Hz, 1H: 5 ε₂), 2.98 (dd,J=12 and 4.5 Hz, 1H: 4 β₂), from 3.20 to 3.40 (mt, 3H: 4 β₁ - 3 δ₁ and1H of the ArCH₂ allyl), 3.25 (s, 3H: NCH₃ 4), 3.48 (dd, J=16 and 6.5 Hz,1H: the other H of the ArCH₂ allyl), 3.56 (mt, 1H: 3 δ₂), 4.57 (dd,J=6.5 and 7.5 Hz, 1H, 3 α), 4.68 (broad dd, J=13.5 and 7.5 Hz, 1H: 5ε₁), 4.84 (mt, 1H: 2α), 4.90 (broad d, J=10 Hz, 1H: 1α), from 5.00 to5.15 (mt, 2H: ═CH₂), 5.23 (broad d, J=5.5 Hz, 1H: 5α), 5.28 (dd, J=12and 4.5 Hz, 1H 4α), from 5.80 to 5.95 (mt, 3H: 6 α-1β and allyl CH),6.53 (d, J=10 Hz, 1H: NH 2), 7.04 (mt, 3H: aromatic H at 4), from 7.15to 7.40 (mt, 5H: aromatic H 6), 7.45 (dd, J=8.5 and 2 Hz, 1H: 1' H₄),7.48 (dd, J=8.5 and 4 Hz, 1H: 1' H--), 7.88 (dd, J=4 and 2 Hz, 1H: 1'H₆), 8.45 (d, J=10 Hz, 1H: NH 1), 8.76 (d, J=9.5 Hz, 1H: NH 6), 11.64(s, 1H: OH).

4-N-Allylammonio pristinamycin I_(A) bromide can be prepared in thefollowing manner:

10 g of pristinamycin I_(A) in solution in 25 cm³ of 1,2-dichloroethaneare placed in a three-necked flask kept under nitrogen atmosphere,followed by 2.5 cm³ of allyl bromide. The mixture is heated for 7 hoursat 40° C. and then stirred at ambient temperature for 14 hours. 200 cm³of toluene are then added with stirring over 10 minutes and the mixtureis stirred for 30 minutes. The precipitate formed is filtered off,rinsed with 50 cm³ of toluene and then dried at reduced pressure (135Pa) at 45° C. to give 10.5 g of a solid which is ground up in 200 cm³ ofethyl acetate at 40° C. and then at ambient temperature for 1 hour. Thesolid is filtered off and then dried at 45° C. at reduced pressure (135Pa) to give 10 g of 4-N-allylammonio pristinamycin IA bromide in theform of a white solid melting at about 210° C.

Proton N.M.R. spectrum (400 MHz, CDCl₃ with addition of a few drops ofCD₃ OD d4, δ in ppm): 0.75 (t, J=7.5 Hz, 3H: CH₃ 2 γ), from 1.00 to 1.35(mt, 3H: 3 β₂ - 3 γ₂ and 5 β₂), 1.18 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from1.45 to 1.65 (mt, 3H: 3 γ₁ and CH₂ 2 β), 1.95 (mt, 1H: 3 β₁) 2.15 (mt,1H: 5 δ₂), 2.28 (broad d, J=16 Hz, 1H: 5 δ₁) 2.55 (d, J=16 Hz, 1H: 5β₁), 2.72 (dt, J=13.5 and 4.5 Hz, 1H: 5 ε₂), 2.95 (s, 3H: NCH₃ 4), from3.10 to 3.50 (mt, 4H: CH₂ 4 β and CH₂ 3 δ), 3.40 and 3.48 (2s, 6H inall: N(CH₃)₂ 4), 4.35 (t, J=7.5 Hz, 1H: 3 α), from 4.40 to 4.60 (mt, 3H:NCH₂ allyl and 5 ε₁), 4.64 (mt, 1H: 2 α), 4.93 (broad s, 1H: 1α), from5.30 to 5.75 (mt, 7H: CH₂ allyl - 5 α - 4 α - 6 α - 1β and allyl CH),6.88 (d, J=10 Hz, 1H: NH 2), from 7.05 to 7.25 (mt, 8H: aromatic H 6 -1' H₄ and 4 δ), 7.35 (dd, J=8 and 4 Hz, 1H: 1' H₅), 7.60 (d, J=8.5 Hz,2H: 4 ε), 7.65 (mt, H: 1' H₆), 8.58 (d, J=9.5 Hz, 1H: NH 6).

EXAMPLE 6

4ε-(2-methylprop-2-en-1-yl) pristinamycin I_(A)

By operating as in Example 5 but starting from 4.31 g of4N-(2-methylprop-2-en-1-yl)ammonio pristinamycin I_(A) chloride and 1.64g of sodium acetate in 40 cm³ of distilled water, 2.45 g are obtained ofa solid which is purified by flash chromatography (50/50 toluene/acetoneeluent) to give 515 mg of 4ε-(2-methylprop-2-en-1-yl) pristinamycinI_(A) in the form of a white solid melting at a temperature higher than260° C.

Proton N.M.R. spectrum (400 MHz, CDCl₃, δ in ppm): 0.45 (dd, J=16 and5.5 Hz, 1H, 5 β₂), 0.90 (t, J=7.5 Hz, 3H: CH₃ 2 γ), from 1.15 to 1.40(mt, 2H: 3 β₂ and 3 γ₂), 1.33 (d, J=7.5 Hz, 3H: CH₃ 1 γ), from 1.55 to1.80 (mt, 3H: 3 γ₁ and CH₂ 2 β), 1.66 (s, 3H: CH₃), from 2.00 to 2.15(mt, 2H, 3 β₁ and 5 δ₂), 2.31 (very broad d, J=16 Hz, 2H: 5 δ₁ and 5β₁), 2.62 (s, 6H: N(CH₃)₂ 4), 2.78 (dt, J=13 and 4 Hz, 1H: 5 ε₂), 2.99(dd, J=12 and 3.5 Hz, 1H: 4 β₂), 3.23 and 3.44 (2d, J=15.5 Hz, 1H each:ArCH₂), 3.27 (s, 3H: NCH₃ 4), 3.32 and 3.56 (2 mts, 1H each: CH₂ 3 δ),3.33 (t, J=12 Hz, 1H: 4 β₁), 4.58 (t, J=7.5 Hz, 1H, 3 α), 4.60 and 4.82(2 broad s, 1H each: ═CH₂), 4.70 (broad dd, J=13 and 7.5 Hz, 1H: 5 ε₁),4.84 (mt, 1H: 2α), 4.90 (broad d, J=10 Hz, 1H: 1α), 5.23 (broad d, J=5.5Hz, 1H: 5α), 5.25 (dd, J=12 and 3.5 Hz, 1H: 4α), 5.87 (d, J=9.5 Hz, 1H:6 α), 5.89 (mt, 1H: 1β), 6.52 (d, J=10 Hz, 1H: NH 2), 7.02 (mt, 3H:aromatic H 4), from 7.15 to 7.40 (mt, 5H: aromatic H 6), 7.45 (broad d,J=8.5 Hz, 1H: 1' H₄), 7.49 (dd, J=8.5 and 4.5 Hz, 1H: 1' H₅), 7.88 (mt,1H: 1' H₆), 8.45 (d, J=10 Hz, 1H: NH 1), 8.76 (d, J=9.5 Hz, 1H: NH 6),11.64 (s, 1H: OH).

4N-(2-Methylprop-2-en-1-yl)ammonio pristinamycin I_(A) chloride can beprepared in the following manner:

In a three-necked flask kept under nitrogen atmosphere are placed 8.66 gof pristinamycin I_(A) in solution in 40 cm³ of dichloromethane and 20cm³ of methanol and then 9.8 cm³ of β-methyllal chloride. The mixture isstirred at reflux for 48 hours and then concentrated at reduced pressure(2.7 kPa) at 30° C. The solid obtained is dissolved in 30 cm³ ofdichloromethane and 300 cm³ of toluene are then added dropwise withstirring. After an hour's stirring the solid obtained is filtered off,rinsed 3 times with 30 cm³ of toluene and then with 50 cm³ of diethylether. The solid is filtered off and then dried at 45° C. at reducedpressure (135 Pa) to give 4.34 g of crude4N-(2-methylprop-2-en-1-yl)ammonio pristinamycin I_(A) chloride in theform of a yellow solid, employed in this form for the preparation of4ε-(2-methylprop-2-en-1-yl) pristinamycin I_(A).

EXAMPLE 7

4ε- (2-RS)-but-3-en-2-yl) pristinamycin I_(A) :

By operating as in Example 5 but starting from 4.8 g of4-N-(buten-2-yl)ammonio pristinamycin I_(A) bromide and 3.69 g of sodiumacetate in 100 cm³ of distilled water, 2.37 g are obtained of a solidwhich is purified by flash chromatography (55/45 toluene/acetone eluent)to give 254 mg of 4ε- (2-RS)-but-3-en-2-yl) pristinamycin I_(A) in theform of a white solid melting at a temperature higher than 260° C.

Proton N.M.R. spectrum (400 MHz, CDCl₃, δ in ppm): the 50/50 mixture ofthe two diastereoisomers is seen. 0.42 and 0.48 (2 dd, J=16 and 5.5 Hz,1H in all, 5 β₂) 0.90 (t, J=7.5 Hz, 3H: CH₃ 2 γ), 1.22 (d, J=7.5 Hz, 3H:CH₃), from 1.15 to 1.40 (mt, 2H: 3 β₂ and 3 γ₂), 1.37 (d, J=7.5 Hz, 3H:CH₃ 1 γ), from 1.55 to 1.80 (mt, 3H: 3 γ₁ and CH₂ 2 β), from 2.00 to2.15 (mt, 2H, 3 β₁ and 5 δ₂), from 2.15 to 2.40 (mt, 2H: 5 δ₁ and 5 β₁),2.62 (s, 6H: N(CH₃)₂ 4), 2.72 and 3.00 (2 mts, 1H in all: 5 ε₂), 3.05and from 3.20 to 3.40 (2 mts, 3H in all: 4 β₂ - 4 β₁ and 3 δ₂), 3.27 (s,3H: NCH₃ 4), 3.57 (mt, 1H: 3 δ₁), 4.10 (mt, 1H: ArCH), 4.60 (t, J=7.5 H,1H, 3 α), 4.64 (broad dd, J=13 and 8 Hz, 1H: 5 ε₁), from 4.75 to 5.55(mt, 6H: ═CH₂ - 2α - 1α - 5 α and 4α), from 5.85 to 6.05 (mt, 3H: 6 α -1β and CH═), from 6.45 to 6.60 (mt, 1H: NH 2), 7.05 (mt, 3H: aromatic H4), from 7.15 to 7.40 (mt, 5H: aromatic H 6), 7.45 (mt, 2H: 1' H₄ and 1'H₅), 7.98 and 8.02 (2 mts, 1H in all: 1' H₆), 8.53 and 8.57 (2d, J=10Hz, 1H in all: NH 1), 8.82 and 8.85 (2d, J=9.5 Hz, 1H in all: NH 6),11.62 and 11.66 (2s, 1H in all: OH).

4-N-(Buten-2-yl)ammonio pristinamycin I_(A) bromide can be prepared inthe following manner:

By operating as in Example 6 but starting from 8.66 g of pristinamycinI_(A), 40 cm³ of dichloromethane, 20 cm³ of methanol and 10.3 cm³ ofcrotyl bromide and after 8 hours' stirring at ambient temperature andthen evaporation, a solid is obtained, which is dissolved in 40 cm³ ofdichloromethane. 400 cm³ of toluene are added dropwise with stirring tothis solution. After an hour's stirring the precipitate obtained isfiltered off, rinsed 3 times with 30 cm³ of toluene and then with 50 cm³of diethyl ether. The solid is filtered off to give 10.7 g of crude4-N-(buten-2-yl)ammonio pristinamycin I_(A) bromide in the form of alight-beige solid employed in this form in the preparation of 4ε-(2-RS)-but-3-en-2-yl) pristinamycin I_(A).

The present invention also relates to the medications consisting of thederivatives of streptogramins according to the invention, in the purestate, used in combination with a derivative of pristinamycin II and/orin the form of a combination with any compatible and pharmaceuticallyacceptable diluent or adjuvant. The medications according to theinvention can be employed orally, rectally or topically.

Tablets, pills, powders or granulates may be employed as compositionsfor oral administration. In these compositions the active product,optionally in the form of a combination, is mixed with one or a numberof inert diluents or adjuvants such as sucrose, lactose or starch. Thesecompositions may also include substances other than diluents, forexample a lubricant such as magnesium stearate.

Compositions for rectal administration are suppositories or rectalcapsules which, besides the active product contain excipients such ascocoa butter, semisynthetic glycerides or polyethylene glycols.

Compositions for topical administration may be, for example, creams,ointments, lotions or aerosols.

In human therapeutics the new streptogramin derivatives according to theinvention are particularly useful in the treatment of infections ofbacterial origin. The doses depend on the effect sought after and theduration of the treatment. The doses are generally between 0.4 and 3.5 gof active product in 2 or 3 portions per day, orally for an adult.

In general, the medical practitioner will determine the posology whichhe or she considers most appropriate as a function of the age, weightand of all the other factors specific to the individual to be treated.

The following example illustrates a composition according to theinvention.

EXAMPLE

Tablets containing a 250 mg dose of active product, which have thefollowing composition, are prepared according to the usual technique:

    ______________________________________                                        4ε-allyl pristinamycin I.sub.A                                                                  250 mg                                              pristinamycin II.sub.B     75 mg                                              excipient: starch, hydrated silica,                                                                     500 mg                                              dextrin, gelatin, magnesium stearate: q.s.                                    ______________________________________                                    

We claim:
 1. A streptogramin derivative of formula (I): ##STR8## inwhich R₁ denotes a methyl or ethyl radical;R₂ denotes a chlorine orbromine atom, or, when R₃ and R₄ are both methyl radicals, R₂ denotes analkenyl radical containing 3 to 5 carbon atoms; and R₃ and R₄ areselected such that one of R₃ and R₄ denotes a hydrogen atom or a methylradical and the other denotes a methyl radical.
 2. A process forpreparing a streptogramin derivative of formula (I) according to claim1, wherein R₂ is a chlorine or bromine atom, said process comprising thestep of reacting the N-halosuccinimide of said streptogramin derivativewith pristinamycin I, wherein R₂ is a hydrogen atom.
 3. A process forpreparing a streptogramin derivative of formula (I) according to claim1, wherein R₂ is an alkenyl radical containing 3 to 5 carbon atoms, saidprocess comprising the step of rearranging, in a basic medium, a saltderived from 4-N-alkenylammonio pristinamycin IA of formula (11):##STR9## in which R₁ is defined as in claim 1; R₅, R₆, R₇ and R₈ areeach independently a hydrogen atom or a methyl radical, provided that atleast two of R₅, R₆, R₇, and R₈ are hydrogen atoms; and X.sup.Θ denotesan anion.
 4. A pharmaceutical composition comprising a pharmaceuticallyeffective amount of at least one streptogramin derivative according toclaim 1, wherein the streptogramin derivative is in the pure state or isin combination with a derivative of pristinamycin II, together with atleast one compatible and pharmaceutically acceptable diluent oradjuvant.